Department of Pediatrics, University of Arizona, Tucson, Arizona, United States of America.
Department of Immunobiology, University of Arizona, Tucson, Arizona, United States of America.
PLoS One. 2022 Aug 18;17(8):e0273075. doi: 10.1371/journal.pone.0273075. eCollection 2022.
The immediate precursor to murine type 1 conventional DCs (cDC1s) has recently been established and named "pre-cDC1s". Mature CD8α+ cDC1s are recognized for suppressing graft-versus-host disease (GvHD) while promoting graft-versus-leukemia (GvL), however pre-cDC1s have not previously been investigated in the context of alloreactivity or anti-tumor responses. Characterization of pre-cDC1s, compared to CD8α+ cDC1s, found that a lower percentage of pre-cDC1s express PD-L1, yet express greater PD-L1 by MFI and a greater percent PIR-B, a GvHD-suppressing molecule. Functional assays were performed ex vivo following in vivo depletion of CD8α+ DCs to examine whether pre-cDC1s play a redundant role in alloreactivity. Proliferation assays revealed less allogeneic T-cell proliferation in the absence of CD8α+ cDC1s, with slightly greater CD8+ T-cell proliferation. Further, in the absence of CD8α+ cDC1s, stimulated CD8+ T-cells exhibited significantly less PD-1 expression compared to CD4+ T-cells, and alloreactive T-cell death was significantly lower, driven by reduced CD4+ T-cell death. Tumor-killing assays revealed that T-cells primed with CD8α-depleted DCs ex vivo induce greater killing of A20 B-cell leukemia cells, particularly when antigen (Ag) is limited. Bulk RNA sequencing revealed distinct transcriptional programs of these DCs, with pre-cDC1s exhibiting activated PD-1/PD-L1 signaling compared to CD8α+ cDC1s. These results indicate distinct T-cell-priming capabilities of murine pre-cDC1s compared to CD8α+ cDC1s ex vivo, with potentially clinically relevant implications in suppressing GvHD while promoting GvL responses, highlighting the need for greater investigation of murine pre-cDC1s.
鼠源 1 型传统树突状细胞（cDC1）的前体细胞最近已经被确定，并被命名为“前 cDC1”。成熟的 CD8α+cDC1 被认为可以抑制移植物抗宿主病（GvHD），同时促进移植物抗白血病（GvL），但之前并未在前 cDC1 中研究其同种异体反应或抗肿瘤反应。与 CD8α+cDC1 相比，对前 cDC1 的特征分析发现，前 cDC1 中表达 PD-L1 的比例较低，但通过 MFI 表达更高的 PD-L1，并且表达更多的 PIR-B，一种抑制 GvHD 的分子。在体内耗尽 CD8α+DC 后进行体外功能测定，以研究前 cDC1 是否在同种异体反应中起冗余作用。增殖测定显示，在缺乏 CD8α+cDC1 的情况下，同种异体 T 细胞增殖减少，而 CD8+T 细胞增殖增加。此外，在缺乏 CD8α+cDC1 的情况下，与 CD4+T 细胞相比，受刺激的 CD8+T 细胞的 PD-1 表达明显降低，同种异体反应性 T 细胞死亡明显降低，这是由 CD4+T 细胞死亡减少驱动的。肿瘤杀伤测定显示，体外用耗尽 CD8α 的 DC 致敏的 T 细胞诱导 A20 B 细胞白血病细胞的杀伤作用更大，特别是在抗原（Ag）有限的情况下。批量 RNA 测序揭示了这些 DC 的不同转录程序，与 CD8α+cDC1 相比，前 cDC1 表现出激活的 PD-1/PD-L1 信号。这些结果表明，鼠源前 cDC1 与 CD8α+cDC1 相比，具有不同的体外 T 细胞致敏能力，这可能在抑制 GvHD 同时促进 GvL 反应方面具有临床相关意义，突出了对鼠源前 cDC1 进行更深入研究的必要性。
